The present invention relates to a composition containing L-ascorbic acid, an L-ascorbic acid derivative or a salt thereof as an active ingredient. The composition of the present invention has the effect of reducing lactic acid levels in blood, and is useful, for example, for reducing side effect caused by a drug which has lactic acidosis as a side effect.
Lactic acidosis is a state in which the lactic acid level in blood is 45 mg/dL or more, and pH of arterial blood is 7.25 or less. As to clinical symptoms, though lactic acidosis usually does not result in any symptoms in the early stage, later there appear, for example, low blood pressure, unconsciousness, nausea, vomiting, stomach ache, diarrhea, muscular ache, the state of hyperventilation and circulatory disorder etc. These symptoms often occur especially severely in elderly persons and patients with cardiac or renal disease etc.
Certain kind of drugs and medical supplements are known to cause lactic acid levels to increase in blood as a side effect and to induce lactic acidosis. After lactic acidosis occurs, usage of the drugs and the medical supplements may be restricted, because of the possibility that they might worsen renal failure etc.
Biguanide compounds have excellent activity in reducing blood sugar levels. Therefore they have long been used as a medicament for treating diabetes, as have sulfonylureas (SU). Since some biguanide compounds have recently been found to have a unique pharmaceutical profile that they do not promote insulin secretion, do not induce fatness, and improve insulin resistance, biguanide compounds such as metformin (1,1-dimethylbiguanide hydrochloride) have been paid attention. However, biguanide compounds are known to cause hyperlactatemia (Brit.Med.J., 5794/1, 205-206(1972)) and lactic acidosis (Acta.Med.Scand., 191, 203-208 (1972)) as a side effect by inducing accumulation of lactic acid. In fact, phenformin (1-(2-phenethyl)biguanide), a biguanide, is known to cause often serious lactic acidosis as a side effect.
A dichloroacetic acid salt of a biguanide compound is reported as a safer drug (JP 51-125718 (A)). However, dichloroacetic acid has comparatively strong toxicity (LD50/rat oral: 2820 mg/kg), so the salt is not a satisfactorily safer drug.
The problem to be solved is to provide a medicament for reducing lactic acid levels in blood, and to provide a pharmaceutical composition or a compound with a reduced side effect, which contains a drug or a medical supplement which causes lactic acid levels in blood to increase as a side effect.
The inventors of the present invention have intensively carried out research on pharmaceutical compositions or compounds for reducing side effect caused by a drug or the like which causes lactic acid levels in blood to increase as a side effect, and found that L-ascorbic acid or the like can reduce lactic acid in blood. Thus, the present invention has been accomplished.
That is, the present invention is as follows.
[1] A medicament for reducing lactic acid levels in blood containing L-ascorbic acid, an L-ascorbic acid derivative or a salt thereof as an active ingredient.
[2] A medicament according to [1] for treating lactic acidosis.
[3] A medicament according to [1] or [2] containing L-ascorbic acid as an active ingredient.
[4] A method for reducing lactic acid levels in blood comprising administrating L-ascorbic acid, an L-ascorbic acid derivative or a salt thereof.
[5] A pharmaceutical composition containing L-ascorbic acid, an L-ascorbic acid derivative or a salt thereof, and a drug or a medical supplement which causes lactic acid levels in blood to increase as a side effect.
[6] A pharmaceutical composition according to [5] wherein the drug or the medical supplement which causes lactic acid levels in blood to increase as a side effect is amoxapine, theophylline, metformin, phenformin, buformin, nalidixic acid, hopantenic acid, azidothymidine or dideoxycytidine or a salt of any of these; or high caloric transfusion, propylene glycol, ethylene glycol, xylitol, lactose or sorbitol.
[7] A pharmaceutical composition according to [5] containing L-ascorbic acid, an L-ascorbic acid derivative or a salt thereof; and a biguanide represented by formula 1: 
wherein
R1 is hydrogen or lower alkyl;
R2 is lower alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted aryloxy-lower alkyl; or R1 and R2 are taken together with the nitrogen atom to form saturated heterocyclic ring, or a salt thereof.
[8] A pharmaceutical composition according to [5], [6] or [7] wherein L-ascorbic acid, the L-ascorbic acid derivative or the salt thereof is L-ascorbic acid.
[9] A pharmaceutical composition according to any one of [5] to [8] wherein the dose of L-ascorbic acid, the L-ascorbic acid derivative or the salt thereof is in the range between about 50 mg/day and about 10 g/day.
[10] A salt formed from L-ascorbic acid or an L-ascorbic acid derivative and a drug having basic group(s) which causes lactic acid levels in blood to increase as a side effect.
[11] A salt according to [10] wherein the drug having basic group(s) which causes lactic acid levels in blood to increase as a side effect is a biguanide represented by formula 1: 
wherein R1 and R2 are as defined above.
[12] A salt according to [10] wherein the drug having basic group(s) which causes lactic acid levels in blood to increase as a side effect is metformin, phenformin or buformin.
[13] A salt according to [10] wherein the drug having basic group(s) which causes lactic acid levels in blood to increase as a side effect is metformin.
[14] A salt according to any one of [10] to [13] wherein L-ascorbic acid, the L-ascorbic acid or the salt thereof is L-ascorbic acid.
[15] A medicament containing a salt according to any one of [10] to [14].
[16] A medicament for treating diabetes containing a salt according to any one of [10] to [14].
[17] A method for treating diabetes comprising administrating a salt according to any one of [10] to [14].
xe2x80x9cL-Ascorbic acid derivativexe2x80x9d includes any L-ascorbic acid derivatives which have a pharmacological effect as Vitamin C, such as esters, stereoisomers, glycosides, aminated derivatives, ethers and the like of L-ascorbic acid (xe2x80x9cUnknown Abilities of L-Ascorbic Acidxe2x80x9d Kumao Ebihara, ed. by Maruzen (1992)).
xe2x80x9cEster of L-ascorbic acidxe2x80x9d includes esters esterified at one or more of 2-, 3-, 5- or 6-hydroxyl group of L-ascorbic acid or stereoisomers thereof, for example, esters of phosphoric acid, sulfuric acid, straight or branched C2-C20 alkanoic acid or aryl carboxylic acid, and esters esterified by straight or branched C2-C6 alkoxycarbonyl and the like. Examples of the straight or branched C2-C20 alkanoic acid are acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, hexanoic acid, octanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid and the like. Preferred example are the straight C12-C20 alkanoic acids. Examples of the aryl carboxylic acid include benzoic acid and the like. Examples of the straight or branched C2-C6 alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl and the like. Preferred examples of the esters of phosphoric acid or sulfuric acid are ones esterified at the 2-hydroxyl group. Preferred examples of the esters of straight or branched C2-C20 alkanoic acid or aryl carboxylic acid, and the esters of straight or branched C2-C6 alkoxycarbonyl are those esterified at the 5- and/or 6-position(s).
xe2x80x9cStereoisomer of L-ascorbic acidxe2x80x9d includes erythorbic acid and the like. xe2x80x9cGlycoside of L-ascorbic acidxe2x80x9d includes glycosides glycosidated at one or more of 2-, 3-, 5- and 6-hydroxyl groups of L-ascorbic acid or stereoisomers thereof, for example, 2-xcex1-glycoside and the like (Biochem. Biophys. Acta, 1035, 44-50 (1990)). xe2x80x9cAminated derivatives of L-ascorbic acidxe2x80x9d include derivatives substituted by amino at one or more of 2-, 3-, 5-and 6-hydroxyl groups of L-ascorbic acid or stereoisomers thereof, for example, scorbamic acid, erythroscorbamic acid and the like. xe2x80x9cEther of L-ascorbic acidxe2x80x9d includes ethers formed at one or more of 2-, 3-, 5- or 6-hydroxyl group of L-ascorbic acid or stereoisomers thereof, for example, ethers of straight or branched C1-C20 alkyl at 5- or 6-hydroxyl groups.
Especially preferred examples of the L-ascorbic acid derivatives are L-ascorbic acid 2-phosphate, L-ascorbic acid 2-sulfate, L-ascorbic acid 6-palmitate, L-ascorbic acid 6-stearate, L-ascorbic acid 2-a-glycoside and the like.
xe2x80x9cSalt of L-ascorbic acid or an L-ascorbic acid derivativexe2x80x9d includes pharmaceutically acceptable salts of L-ascorbic acid and L-ascorbic acid derivatives. Examples of such salts are alkaline metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as magnesium salt, calcium salt, barium salt and the like; ammonium salts and the like.
L-Ascorbic acid, an L-ascorbic acid derivative or a salt thereof may be in the form of a solvate such as a hydrate and the like.
xe2x80x9cDrug which causes lactic acid levels in blood to increase as a side effectxe2x80x9d includes drugs which cause lactic acid levels in blood to increase as a side effect when administered, especially drugs which cause lactic acidosis by administration. Examples are amoxapine (psychotropic agent), theophylline (antitussive; expectorant), nalidixic acid (chemotherapeutic), calcium hopantenate (brain metabolic stimulant), azidothymidine, dideoxycytidine (HIV reverse transcriptase inhibitor), biguanides represented by formula 1: 
wherein R1 and R2 are as defined above, or a salt thereof, for example, metformin, phenformin, buformin ((1-butylbiguanide): medicament for diabetes) and the like, and the like. Those drugs and the salts thereof may be in the form of a solvate such as a hydrates and the like.
xe2x80x9cMedical supplement which causes lactic acid levels in blood to increase as a side effectxe2x80x9d includes medical supplements which are administered to maintain living bodies without pharmaceutical effects and which cause lactic acid levels in blood to increase as a side effect on administration, especially medical supplements which cause lactic acidosis on administration. Typical examples are high calorie transfusion, propylene glycol, ethylene glycol, pentoses such as xylitol, lactose, sorbitol and the like (xe2x80x9cIgaku no ayumixe2x80x9d, 183, 617(1997)) and the like.
xe2x80x9cLower alkylxe2x80x9d includes straight or branched C1-C6 alkyl. Typical examples are methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 3-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl and the like.
xe2x80x9cArylxe2x80x9d includes C6-C10 aryl. Typical examples are phenyl, naphthyl and the like.
xe2x80x9cAralkylxe2x80x9d includes C7-C15 aralkyl. Typical examples are benzyl, phenylethyl, naphthylmethyl, naphthylpropyl and the like.
xe2x80x9cAryloxy-lower alkylxe2x80x9d includes lower alkyl substituted by aryloxy. Typical examples of the aryloxy are phenoxy, 1-naphthoxy, 2-naphthoxy and the like. Typical examples of the aryloxy-lower alkyl are 2-phenoxyethyl, 2-phenoxypropyl, 3-phenoxypropyl, 4-phenoxybutyl, 5-phenoxypentyl, 6-phenoxyhexyl, 2-(1-naphthoxy)ethyl, 2-(1-naphthoxy)propyl, 3-(1-naphthoxy)propyl, 4-(1-naphthoxy)butyl, 5-(1-naphthoxy)pentyl, 6-(1-naphthoxy)hexyl, 2-(2-naphthoxy)ethyl, 2-(2-naphthoxy)propyl, 3-(2-naphthoxy)propyl, 4-(2-naphthoxy)butyl, 5-(2-naphthoxy)pentyl, 6-(2-naphthoxy)hexyl and the like.
The substituent of xe2x80x9csubstituted aryl, substituted aralkyl and substituted aryloxy-lower alkylxe2x80x9d includes hydroxy, halogen atom, lower alkyl, lower alkoxy, amino, aminocarbonyl, aminosulfonyl, benzyloxy, phenyl, phenoxy, 2-phenylethyloxy, 3-phenylpropyloxy, cyano, nitro, acyl, acyloxy and the like. The position(s) of the substituent(s) on aralkyl and aryloxy-lower alkyl are preferably any position(s) on the aryl moiety. The number of the substituent(s) is 1 to 5, preferably 1 to 3.
Typical examples of the substituted aryl are 2-nitrophenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 4-methoxycarbonylphenyl, 4-cyanophenyl, 4-methylphenyl, 3,4-difluorophenyl, 4-bromophenyl, 4-(N,N-dimethylaminocarbonyl)phenyl, 4-(N,N-dimethylaminosulfonyl)phenyl, 4-benzyloxyphenyl, 4-hydroxyphenyl, 4-biphenyl, N,N-dimethylaminophenyl, 3-phenoxyphenyl, 3-(2-phenylethyloxy)phenyl, 3-(3-phenylpropyloxy)phenyl and the like.
Typical examples of the substituted aralkyl are 2-nitrobenzyl, 4-methoxybenzyl, 2,3-dimethoxybenzyl, 2,3,4-trimethoxybenzyl, 4-methoxycarbonylbenzyl, 4-cyanobenzyl, 4-methylbenzyl, 3,4-difluorobenzyl, 4-bromobenzyl, 4-(N,N-dimethylaminocarbonyl)benzyl, 4-(N,N-dimethylaminosulfonyl)benzyl, 4-benzyloxybenzyl, 4-hydroxybenzyl, 4-phenylbenzyl, N,N-dimethylaminobenzyl, 3-phenoxybenzyl, 3-(2-phenylethyloxy)benzyl, 3-(3-phenylpropyloxy)benzyl, 2-(2-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(2,3-dimethoxyphenyl)ethyl, 2-(2,3,4-trimethoxyphenyl)ethyl, 2-(4-methoxycarbonylphenyl)ethyl, 2-(4-cyanophenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(3,4-difluorophenyl)ethyl, 2-(4-bromophenyl)ethyl, 2-(4-(N, N-dimethylaminocarbonyl)phenyl)ethyl, 2-(4-(N,N-dimethylaminosulfonyl)phenyl)ethyl, 2-(4-phenylethyloxyphenyl)ethyl, 2-(4-hydroxyphenyl)ethyl, 2-(4-phenylphenyl)ethyl, 2-(N,N-dimethylaminophenyl)ethyl, 2-(3-phenoxyphenyl)ethyl, 2-(3-(2-phenylethyloxy)phenyl)ethyl, 2-(3-(3-phenylpropyloxy)phenyl)ethyl and the like.
Typical examples of the substituted aryloxy-lower alkyl are 2-(2-nitrophenyl)oxyethyl, 2-(4-methoxyphenyl)oxyethyl, 3-(4-methoxyphenyl)oxypropyl, 2-(2,3-dimethoxyphenyl)oxypropyl, 3-(2,3,4-trimethoxyphenyl)oxypropyl, 2-(4-methoxycarbonylphenyl)oxyethyl, 2-(4-cyanophenyl)oxyethyl, 4-(4-methylphenyl)oxybutyl, 2-(3,4-difluorophenyl)oxyethyl, 2-(4-bromophenyl)oxyethyl, 5-(4-(N,N-dimethylaminocarbonyl)phenyloxypentyl, 2-(4-(N,N-dimethylaminosulfonyl)phenyl)oxyethyl, 2-(4-benzyloxyphenyl)oxyethyl, 2-(4-hydroxyphenyl)oxyethyl, 2-(4-phenylphenyl) oxyethyl, 2-(N,N-dimethylaminophenyl)oxyethyl, 2-(3-phenoxyphenyl)oxyethyl, 2-(3-(2-phenylethyloxy)phenyl)oxyethyl, 2-(3-(3-phenylpropyloxy)phenyl)oxyethyl and the like.
L-Ascorbic acid, L-ascorbic acid derivatives and the salts thereof have inhibitory effect against gluconeogenesis as shown in Experiment 5, and they can enhance the inhibitory effect against gluconeogenesis of biguanides represented by formula 1 which are useful as a medicament for diabetes. Therefore, xe2x80x9cthe pharmaceutical composition containing L-ascorbic acid, an L-ascorbic acid derivative or a salt thereof and a biguanide represented by formula 1 or the salt thereofxe2x80x9d and xe2x80x9cthe salt formed from L-ascorbic acid or an L-ascorbic acid derivative and a biguanide represented by formula 1xe2x80x9d are useful as medicaments for treating diabetes.
xe2x80x9cSaturated heterocyclic ring which R1 and R2 are taken together with the nitrogen atom to formxe2x80x9d includes 3- to 7-membered, nitrogen-containing saturated heterocyclic rings containing at least one nitrogen, sulfur or oxygen atom. Typical examples include 3-membered nitrogen-containing saturated heterocyclic rings such as aziridine and the like; 4-membered nitrogen-containing saturated heterocyclic rings such as azetidine and the like; 5-membered nitrogen-containing saturated heterocyclic rings such as imidazolidine, pyrrolidine, pyrazoline, thiazolidine, oxazolidine and the like; 6-membered nitrogen-containing saturated heterocyclic rings such as piperidine, piperazine, morpholine and the like; 7-membered nitrogen-containing saturated heterocyclic rings such as homopiperidine and the like; and the like.
The salts of xe2x80x9camoxapine, theophylline, metformin, phenformin, buformin, nalidixic acid, hopantenic acid, azidothymidine, dideoxycytidine or a biguanide represented by formula 1xe2x80x9d include pharmaceutically acceptable salts thereof. Typical examples include salts with inorganic acids such as the hydrochloride, sulfate, hydrobromide, phosphate salts and the like; salts with organic acids such as the oxalate, malonate, fumarate, benzenesulfonate, methanesulfonate salts and the like; salts with inorganic bases such as the sodium, potassium, calcium, barium, ammonium salts and the like; salts with organic bases such as the lysine, triethylammonium salts and the like. The salt may be in the form of a solvate such as a hydrate and the like.
The basic group in xe2x80x9cdrug having basic group(s) which causes lactic acid levels in blood to increase as a side effectxe2x80x9d includes basic groups which are able to form salts with L-ascorbic acid or L-ascorbic acid derivatives. Typical examples include optionally substituted amino, optionally substituted cyclic amino, hydroxyamino, optionally substituted guanidino, optionally substituted amidino and the like.
xe2x80x9cCyclic aminoxe2x80x9d includes 3- to 7-membered cyclic amino containing at least one of nitrogen, sulfur and oxygen atoms. Typical examples include 3-membered cyclic amino such as aziridinyl and the like; 4-membered cyclic amino such as azetidinyl and the like; 5-membered cyclic amino such as imidazolidinyl, pyrrolidinyl, pyrazolinyl, thiazolidinyl, oxazolidinyl and the like; 6-membered cyclic amino such as piperidinyl, piperazinyl, morpholinyl and the like; 7-membered cyclic amino such as homopiperidinyl and the like; and the like.
The substituent of xe2x80x9csubstituted amino, substituted cyclic amino, substituted guanidino and substituted amidinoxe2x80x9d includes lower alkyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted aryloxy-lower alkyl and the like. They may be substituted by two substituents.
Typical examples of substituted amino include methylamino, dimethylamino, ethylamino, diethylamino, butylamino, benzylamino, 4-aminobenzylamino, 3-methoxybenzylamino, 2-phenylethylamino and the like.
Typical examples of substituted guanidino include methylguanidino, dimethylguanidino, ethylguanidino, diethylguanidino, butylguanidino, benzylguanidino, 4-aminobenzylguanidino, 3-methoxybenzylguanidino, 2-phenylethylguanidino and the like.
Typical examples of the substituted amidino are methylamidino, dimethylamidino, ethylamidino, diethylamidino, butylamidino, benzylamidino, 4-aminobenzylamidino, 3-methoxybenzylamidino, 2-phenylethylamidino and the like.
Preferred examples of the xe2x80x9csalt formed from L-ascorbic acid or an L-ascorbic acid derivative and a drug having basic group(s) which causes lactic acid levels in blood to increase as a side effectxe2x80x9d include xe2x80x9csalts formed from L-ascorbic acid or an L-ascorbic acid derivative and a biguanide represented by formula 1xe2x80x9d, and more preferred are xe2x80x9csalts formed from L-ascorbic acid or an L-ascorbic acid derivative and metformin, buformin or phenforminxe2x80x9d. Typical examples include metformin L-ascorbate, metformin L-ascorbic acid 2-phosphate, metformin L-ascorbic acid 2-sulfate, metformin L-ascorbic acid 6-palmitate, metformin L-ascorbic acid 6-stearate, buformin L-ascorbate, buformin L-ascorbic acid 2-phosphate, buformin L-ascorbic acid 2-sulfate, buformin L-ascorbic acid 6-palmitate, buformin L-ascorbic acid 6-stearate, phenformin L-ascorbate, phenformin L-ascorbic acid 2-phosphate, phenformin L-ascorbic acid 2-sulfate, phenformin L-ascorbic acid 6-palmitate, phenformin L-ascorbic acid 6-stearate and the like.
The biguanide represented by formula 1 can be produced for example by the following method: 
wherein R1 and R2 are as defined above.
The hydrochlorides of the biguanides represented by formula 1 can be produced, for example, by heating a mixture of a compound represented by the formula: R1R2NH HCl and dicyandiamide at 120xc2x0 C. or above without or in a solvent. Preferred reaction solvents are high-boiling point ethers such as methyl cellosolve and the like. The hydrochloride of biguanide of formula 1 can be changed to free base or another salt by a conventional method. The free base of biguanide of formula 1 can be produced for example by letting the hydrochloride flow through ion exchange resin column according to the method described in JP 50-53520 (A). The free base can be also produced by neutralizing the hydrochloride by sodium hydroxide solution or the like and concentrating the mixture in vacuo, followed by extraction from the residue with an organic solvent such as acetone.
xe2x80x9cSalt formed from L-ascorbic acid or an L-ascorbic acid derivative and a drug having basic group(s) which causes lactic acid levels in blood to increase as a side effectxe2x80x9d can be produced by a conventional method. The salt can be formed for example by mixing L-ascorbic acid or an L-ascorbic acid derivative and xe2x80x9ca drug having basic group(s) which causes lactic acid levels in blood to increase as a side effectxe2x80x9d in an inactive solvent. The inactive solvents include alcohols such as methanol, ethanol, 2-propanol and the like, water, acetone, mixtures of any of these and the like. The amount of L-ascorbic acid or an L-ascorbic acid derivative is selected for example from about 0.3 to about 3 equivalent, preferably about 1 to about 1.5 equivalent, per 1 equivalent of the xe2x80x9cdrug having basic group(s) which causes lactic acid levels in blood to increase as a side effect.xe2x80x9d
When such a salt can be easily crystallized, the salt may be produced in a crystalline form, and may be purified by recrystallization if needed. Solvents for recrystallization include alcohols such as methanol, ethanol, 2-propanol and the like, ethers such as diethyl ether and the like, esters such as ethyl acetate and the like, aromatic hydrocarbons such as toluene and the like, ketones such as acetone and the like, hydrocarbons such as hexane and the like, water and mixture of any of these and the like.
The salt formed from L-ascorbic acid or an L-ascorbic acid derivative and a biguanide of formula 1 can be produced in a crystalline form for example by mixing L-ascorbic acid or the L-ascorbic acid derivative and the free biguanide in an inert solvent. The amount of L-ascorbic acid or the L-ascorbic acid derivative is preferably about 1 to about 1.5 equivalent per 1 equivalent of the biguanide of formula 1. Inert solvents include alcohols such as methanol, ethanol, 2-propanol and the like, water, acetone and mixture of any of these. The crystallization temperature is for example about xe2x88x9220 to about 70xc2x0 C., preferably about xe2x88x9210 to about 20xc2x0 C.
An xe2x80x9cL-ascorbic acid, an L-ascorbic acid derivative or a salt thereofxe2x80x9d as a medicament for reducing lactic acid levels in blood, xe2x80x9ca pharmaceutical composition containing L-ascorbic acid, an L-ascorbic acid derivative or a salt thereof, and a drug or a medical supplement which causes lactic acid levels in blood to increase as a side effectxe2x80x9d and xe2x80x9ca salt formed from L-ascorbic acid or an L-ascorbic acid derivative and a drug having basic group(s) which causes lactic acid levels in blood to increase as a side effectxe2x80x9d may be administered orally or parenterally. Pharmaceutical forms for oral administration include generally acceptable forms, for example, tablets, capsules, granules, fine granules, powders, pills, syrups, suspensions and the like. Pharmaceutical forms for parenteral administration include for example injections such as solutions, emulsions, suspensions and the like; suppository for administration through the rectum; dermal preparations and the like. These compositions can be prepared by mixing the active compound with conventional carriers, excipients, binders, stabilizers and the like. Injections may contain buffers, solubilizers, agents for influencing osmotic pressure and the like.
The dose for administration of xe2x80x9cL-Ascorbic acid, an L-ascorbic acid derivative or a salt thereofxe2x80x9d as a medicament for reducing lactic acid levels in blood generally varies depending on the severity of the symptoms, the patient""s age, body weight, administration route and the like. L-Ascorbic acid, L-ascorbic acid derivatives and salts thereof are usually administered to an adult (body weight: 60 kg) in a dose of about 50 mg to about 10 g, preferably about 100 mg to about 5 g, more preferably about 300 mg to about 3 g per day in one portion or several portions.
The dose for administration of xe2x80x9cpharmaceutical composition containing L-ascorbic acid, an L-ascorbic acid derivative or a salt thereof, and a drug or a medical supplement which causes lactic acid levels in blood to increase as a side effectxe2x80x9d generally varies depending on the severity of the symptoms, the patient""s age, body weight, administration route and the like. L-Ascorbic acid, an L-ascorbic acid derivative or a salt thereof in the pharmaceutical composition is usually administered to an adult (body weight: 60 kg) in a dose of about 50 mg to about 10 g, preferably about 100 mg to about 5 g, more preferably about 300 mg to about 3 g per day in one portion or several portions. A drug or a medical supplement which causes lactic acid levels in blood to increase as a side effect in the pharmaceutical composition may be administered in the usual dose in which the drug or the medical supplement has their own effects. When the drug is a biguanide represented by formula 1 or the salt thereof, the drug is usually administered to an adult (body weight: 60 kg) in a dose of about 100 mg to about 5 g, preferably about 300 mg to about 3 g, more preferably about 500 mg to about 2 g per day in one portion or several portions.
The dose for administration of xe2x80x9csalt formed from L-ascorbic acid or an L-ascorbic acid derivative and a drug having basic group(s) which causes lactic acid levels in blood to increase as a side effectxe2x80x9d generally varies depending on the severity of the symptoms, the patient""s age, body weight, administration route and the like. The salt may be administered in the usual dose in which xe2x80x9cthe drug having basic group(s) which causes lactic acid levels in blood to increase as a side effectxe2x80x9d contained in the salt has its own effects. However, when the amount of xe2x80x9cL-ascorbic acid or an L-ascorbic acid derivativexe2x80x9d contained in the salt is lower than the necessary dose for reducing lactic acid levels in blood, additional xe2x80x9cL-ascorbic acid, an L-ascorbic acid derivative or a salt thereofxe2x80x9d may be administered together. When the salt is xe2x80x9csalt formed from L-ascorbic acid or an L-ascorbic acid derivative and a biguanide represented by formula 1xe2x80x9d, the salt is usually administered to an adult (body weight: 60 kg) in a dose of about 100 mg to about 20 g, preferably about 200 mg to about 10 g, more preferably about 600 mg to about 6 g per day in one portion or several portions.